Celecoxib Clinical Efficacy and Safety

---

Celecoxib - Clinical Objectives

Indications Differentiation

● Osteoarthritis ● Gastrointestinal

● Rheumatoid c PlateletArthritis

● Generai Safety● Management

of Pain

CelecoxibClinical Efficacy and

Safety



●

✎

✎

Osteoarthritis ● Gastrointestinai

Rheumatoid ● Platelet

Arthritis● General Safety

Managementof PGn

3 . . . -c—

K . . ..-c—

Hypothesis

Specific inhibitors of COX-2 wiil be

anti-inflammatory and analgesic without

the typical side-effects of NSAIDS

19 . . ..-—

●

●

●

●

●

Studies: 51

Patients/Subjects: 13,072

Endoscopy: >4,700 patiants

No. Patients with z 1 Year Exposure:

981- NDA

2,443- Safety Update

Patient Years: 3,263- NDA5,005- Safety Update

A . . ..-—

Pivotal OA Studies

● 12-week studies

-2 knee

-1 hip

s 6-week studies

-2 knee

6 ..” -—

-. .

1

Design: 12-Week Studies

Ptambo BID

Ceiecoxib W MS BID

Ostewthritis Flare Cetecoxib 100 q BID

c0b20xib 200 mg Blo

NaproxenSKIMS SID

I I (

Week O 2 6 12

Arthritis A8eesemmfs X X x x

7 . . . -—

12-Week OA Studies

Study No.

020 021 054index Joint Knee Knee ~ Total.—

Treatment Group (n)Placebo 204 242 218 6S4Celecoxib 50 mg BID 203 252 216 671Celecoxib 100 mg BID 197 240 207 644Celecoxib 200 mg BID 202 233 213 648Naproxen 500 mg BID 198 226 207 631

Total 1004 1163 1081 3258

Phl”d Umpl. dlo -W,rwp

9 .*. ,*c—

Patient’s Assessment of Pain

* PI.* + C4-wxlb IW w 010 + W?-- 500m, W+ Cohcoxib W q W + ~’lb W m, BID

-m.

026 12

weeksStudy 020 (Knee)

Measures of OA Efficacy

● Patient’s Assessment of Pain (VAS)

● WOMAC OA Index

- Pain

- Function

- Stiffness

● Patient’s Global Assessment

● Physician’s Global Aasesament

c SF-36 Health Survey

R . . . -—

Patient Disposition: 12-Week Studies

Comphtwl Trutmmt A&+.w mhuFailurm EWII1

Pedd d.u WtiMmw81s, S@,ifica.dy dltkmn I from mube; .05

10. . ..-—


+ %* 4- chz~ !wq DID+ NW.=.”w ., IID-e. ~,11 W., SID + Cdaco.iS200m, BID

~l~;f~

o’~ 0 ~

Ozc tao26 12Weeb

Study 020 (Knee) Study 021 (Knee)w.. C-lm

12. . . -s

2

.4


4 Pl”.b ++ 2dscoxlb30.,2JD +

C.kdb 124 .-q 810Coheoxlb 200q BD

+ NapommSm., 2m

> o-i o“~ o“~026 1202s 12026 12

weeka

Study 020 (Knee) Study 021 (Knee) Study 0S4 (HiP)Sd9. o.lw4“ . . . ..4”.7c—

HiP OA pivotal Study -054

SF-36 - Physical Health Domains

❑ PMc.b [“.2W

207❑ Cakdb50m, BID(“.W

. ❑ Coh.xib W m, 810(11.20?Im, BID [N2?zl

@ 15 ** 010{..20Tj

? ,~

8C5s=0

‘5] Phy,lcd Rolm wn~ GummlFunctkMng Phydaal Pain H.dth

24.. O.ICU. WTlfkuWdlfhrml Iran PIacW P 4.0S

1s . . . -,—

..—.

6-Week OA Studies

Study NO.

0s0 oa7Index Jo}nt Knee Knee Totel

——Treatment Group (n)

Placebo 232 244 476Celecoxlb 100 mg BID 231 243 474Celecoxlb 200 mg QD 223 231 454

Total 666 718 1404

WOMAC - Physical Function

* Fi..ta * CdmembIoa .* BID + *.-I! w ., m* Cdmn.b w .,210 + Cdwo,b 2Ww BID

ml ml %

0“~ o-~ ~-+n——0’2 1202 12 02 12

weeks

Study 020 (Knee) Study 02t (Knee) study 054 (Hip)&ol.. B.##

1A . . . M.. —


Placebo S10

Oeteoarthtitiz flare C4acoxib 100 me BID

\ Calacoxibmomglxl

Week O 2 a

~dtii Asaeasrmnts X x x

*R . . . ..x —


Complslwl Twtmat A#vusa OlhwFdlum Event

M- *.I4Wthdl-ewmls

, Zifl.lfl*Ky duhr.+ lm. FhO+ @nt

In . . ..-—

----

3

-—x

1Patient’s Assessment of Pain

m6r:70

bg“~40> lb

* P!.*

* C*.* !00 m, BID

‘1 * Oak.xlb w ., ao

o~ o~6 6

WaekaSludy 060 (Knes) study 067 (KIWO)

scale.o.,win . . . -c—

Conclusions: Celecoxib in OA

c Effective in OA

● Recommended dose

-200 mg per day

-Can be administered insingle or divided doses

c Efficacy similar to naproxen

Design: 12-Week RA Studies

P!aoObO ❑ lo

=Week O 2 6 12

ArlMitis A66uwnent6 X X x x

-9 m.. *r—

WOMAC - Physical Function at Week 6

=1 =1

J--L20

. .

26#

o -Llmmg Xclmg

BID ao

Cduoxlb

I Study 0S0(Knee) Study 0S7 (Knee) I$eml.. 0-18

. Si$mifles.d” difl.mm fromE4at.bo bud m .hw. Ifcm O...li:.: F .+.E1

20 . . . -—



* Osteoarthritis ● Gastrointestinal

● Rheumatoid ● PlateletArthritis

c General Safety● Management

of Pain

22 . . .. A-—

Measures of RA Efficacy

● AC R-20

● Number of Swollen Joints

● Number of Tender/Painful Joints

● Patient’s Global Assessment ofArthritis

● Physician’s Global Assessmentof Arthritis

● SF-36 Health Survey

7A ..”. -—

.4!-=%

.-’%

12-Week RA Studies

Treatment Group (n)PlaceboCelecoxib 100 mg BIDCelecoxib 200 mg BIDCelecoxib 400 mg BiDNaproxen 500 mg BID

Total

mm..d‘mph 9im.zm~p

Study No.

022 023 Total-. _

231 221 452240 228 468235 219 454218 2f7 435225 218 443

1149 1103 2252

9K .*...- c.-

Ptwa

ACR-20 at Week 12

Sludy023

II

.

Ill.

2oe 400504

Cdscoxib NaPmxbn(mg BID) [mg BID)

- ~stik.dy difl..nl Imm FJ”+ , AM

77 . . ..-c—

Number of Swollen Joints* PI”* & C4csxib Z@ m, W + NmF.rL.,ul ion., BID

+ C,lnexlb w w DID + Cdn.xlbanm,mm

24, 24,

o~2 w~12

study 022weeke

study023

u Id”l, “wMd [ml”d*. hi@

9a . . ..-.—


mBID [H)

!250BID{&)

110 (M43q

iBID [“da)

~40z$20

0Camplotwl Trodmmt Adwrw Othm

Failure Ewmt

ACR-20 at Week 12

study 022‘1 ‘1

study 023.

P!ac*bo lcd m 400 5CQ P18c.ba 100 200 400 200

Cbluoxlb Napmxu! Cduoxib t4apmx4n(me BID) (mg BID) (mg 010) (mg 80)

. .5iwwk.ntFjWu..t mm pimbq p <O,w“ !41$m?hniiydlfhra?them. .koxib 100 mg S1% P 4,01

m m.”.M.— —

Pivotal RA Study -033

SF-36 - Physical Health Domains❑ PI* [Ma,,

20a cdoGOxmtoor“, am [n.aaq

mgBID(n.2!1)m, mD(dt?J

& 15 m, IID (n&l 8)

g 10

~:

‘5 ] Ph~kd FM* aOdlW GonwslPurwtlonlng Physkd Pain HMith

.n.

5

Design: 6-Month RA Study

Ceiecoxib2C0mg BID

RheumatoiklArthritl,

syrnptometk Diclofenac SR 75 mg END

I I I I I IWeek O 4 812162024

Arthrlth Aeeeesrnents X X X X X )( X

31 ..” ---

Conclusions: Celecoxib in RA

I ● Effective in RA

● Recommended dose

-100 mgBID-_

- Some patienta may benefii byincreasing the dose to amaximum of 200 mg BID

● Efficacy similar to naproxen

● Sustained efficacy

L 33 ..” *..-

Pain Program

..-..=-m ; .,,.. DModel # 1

ACUTE PAIN(O-24 HOURS)

. Poet-dental surgeq-3 pivotal etudles

- single dose

● Poet-orthopedic surgery-1 supporting study

- repast does

35 . . . -—

6-Month RA Study

Tender/Painful Joints* Swollen Joints@

o~812162024

0 ~4

weeks. Si,mfimti” dlfr.mrdLml”d.bfi pd.cd. u jdnll mz!,lind. M id.lo umnln.d (-dud.. Nw]

32 ..”. *—




c Rheumatoid ● PlateletArthritis

● General Safety● Management

of Pain

- acute pein

- short term psin

- chronic arthritis pain

Pain Program

-~~f ,.*. oModel#1 Modei # 2

ACUTE PAIN SHORT TERM PAIN(O -24 HOURS) (1 -7 OAYS)

● Post-dental surgery ● OA flare-3 piVOtSl studies .3 pivotal studies

- single dose - multiple dose

. Post-orthopedic surgery-1 supporting study

- repeat does

..-.

Model # 1

Design: Post-Dental Surgery Studies

Cetecoxib 28-400 mg

surgery NSAID

P12ab0I 1

Hour O 12 2;

PainAssessments . . . . . . . . . . . . . . . . .

Model # 1Post-Dental Surgery Studies

Study No.

025 027 070 Total.— .—Treatment Group (n)

Placebo 50 55 50 155Celecoxlb 100 mg .. 55 50 105Celecoxlb 200 mg 50 56 50 156Ibuprofen 400 mg 50 -- - 50Neproxen Na 550 mg - 54 35 S9

39. ...*=

ModeI #1TOTPAR(12) Scores

study 025 Study 027 study 070m =, .

se,..25 2s

1

25

20 20

E

15 15

10 10

s s s

0 0 0

Pllubomw Plumtmlm 200 220 Phab0m02ms20

Model # 1Measures of Efficacv

●

●

●

Time to Onset of Pain Relief

Time Specific Pain Relief

Duration of Pain Relief

38. . . -—

Model # 1Time Specific Pain Relief

* Pi..ba

+ cd--b Iw ., so

—.. —1, -.---+

-& WowxlbW m SD +

+ Nwr.xw * 510 sw S9

—.. +

-=-l—,. +---- -.+

- Ibupreh. 4M m$ 50

Houm

-.,., study025 study 027 study 070m.— - m- h.. W WMAn ..m. *—

Model # 1- Supporting StudyDesign: Post-Orthopedic Surgery Study

Plecebo QID PRN

~

PainAeeessnwnte . . . . . . . . . . . . . ..* .

A9 . . ..-—

7

Model # 1Dosing Regimen: Post-Orthopedic Surgery Study

mslRUsQsmmmQse IMzl&semULwQ4a

Da.-vocet UIW + + + +

Ceiecoxib200nq + + Pbo Pbo

Celecexlb 100 v + + PbO PbO

Placobe Pbo PbO Pbo Ptro

Remn4imtlon was allowad 24 hews aftsr tha lint doao of aludy medication

43. . . ..-—

Pain Program

Model # 1 Model # 2ACUTE PAIN SHORT TERM PAIN

(O-24 HOURS) (1 -7 DAYS)

. Post-dental surgery . OA flara.3 pivotal studies .3 pivotal studies

- single dose - mu ftlple dose

● Post-orthopedic surgery-1 supporting study

- repeat dose

45 . . ..*.—

Model # 2Design: Three Pivotal 12-Week OA Studies

PiacOba610

*Oayol 234567

APS pain meesuraa xx Xxx xxx

47 *.. %—

Model # 1lime Specific Pain Relief

* PI.* (.+ + C.1.n.b m M, am {mu)

+C.1.=4.ib ,W m+ 810 (*M) + Dumcu.rl 100 MI w [MI)

1.5-

1.o-

o.!-&

0+ /i—0246 10

H&rs12 18 24

s..”.,.,B“..a-.wkws?dm ikim. ””r”phtpkt.k..m

. . . . . *—

Model # 2Rationale: OA Flare Pain Model

—

● Pain is the primary symptom of OA

● Non-anti-inflammatory analgesics(e.g., acetaminophen and opiates)are efficacious in treating OA pain

● OA model has been used toevaluate the efficacy of a variety ofanalgesics including opiatee andcsntrally acting analgesics

BMW.JO, Ormdl KB, N EIYIJ Wd ! WI : 32J:J7-41Jm”% EM., QI”AoI% P., tig k“, 1ss4: [111.21#

46m.w.-—

Model # 2American Pain Society (APS) Pain Measure

1. Have you experienced any psin in the last 24 hrs?

2. How much pain are you having right now?

3. Indicate the worst pain you have had In the pact24 bra.

4. Indicste the average level of pain you hsvs had inthe paat 24 hrs.

5. Indicate how pain has interfered with function.

~auk-w m I*S, vd nb, N. n

.- . . . ..-—

—

8

Model # 2 Model # 2Average Pain in Past 24 Hours Average Pain in Past 24 Hours

* M.* + cACOIib !00 ., BID * N-mm Sm ., MO

* Cd.emib 20 m, 010* P1.Oba * Cti.b Io!m, ma

+ C.IU.*!4 206., BID+Nwmxm!2W w 21D

* Cdwm,b w .C *O + cd9s0. h ‘M m, BID

7.WI m

.= -

j’

is: k :: ,~lG

?t, o~,

Day

Study 020 (Knee)Day

Study 020 (Knee)*.m. *,#

Study 021 (Knee)

. 0“. I.dle.b.W.~.lk dwilb mnf dlflwum. lrmm pk.w Pam2DW. . &lo

49. 2us Indom. .tad.tkd .;q.,fk.nl dll”m.. hem

MI-------- 50 . . ..-—

Modei # 2Average Pain in Past 24 Hours

* P!”.* + Cokoxlb !W m, SD -w NSp+Oxnl Sm ., m* Cmlue.h 50 mlg BID + CdmozlbSW m, BID

~]~)~]~4

stay

Study 020 (Knee) Study 021 (Knee) study 054 (Hip)2C.”. &uSB“. Ind!!. b ,W4th,l ddlk,., dill”-. from.hti P .o,c+

51 . . ..-c—



● Osteoarthritis ● Gaatrointastinal



of Pain

53 . . . -—

Celecoxib in Analgesia● Efficacy was demonstrated by rep Iicate

studies:

- Model #1: acute pain -3 post-dentalsurgery studies; single dose

- Model #2: short term pain -3 OA flarestudies; multiple dose over several days

● Recommended dose:

-100 mg or 200mg BID

- For acute psin, the second dose may beadministered aa early aa 4 hrs

52 . . ..-—

Safety Database

ActiveP= Celecoxib Control— .

Pharrnazotdnetic Studies 2s1 1,022 2s0

Andwia Sludi*s 30s 74a 2ss

North American Adhrhia Trials 1,834 5,704 27ss

In*rnztional Arthritis Trisl o S73 mo

Lang-tmm Open Labd Atihzitk - 4,4ss -—. _

2,4s0 12,s4a 3,343

-=_~_Total

.13,072 unlqu $@utwamls

Gi *... -—

.--%

9

General Safety Analyses

.

.

.

Serious adverse events and deaths

Incidence of adverse events andwithdrawals:

- North American Arthritis Triale

- Long-term Open Label ArthritisTrial

Laboratory results

55 . . . -c—

Deaths Incidenm, No. (%)Eventstl 00 patbnt-yrs

Deaths

AcrwePlacabO Cebcoxib” Control(n=2450) (n.12,646) (ndl)q

—— .

0 (0.0) 22 (02) 4 (0.1)0.0 0.5 0.7

Cardbvaacubr dsatha, No. (%) o (0.0) 16 (0.1) 2 (0.1)Events/tOO patbnl.ym 0.0 0.3 0.4

I .M **.

57 ..” .-—

North Anmican AritvNls Trials

Adverse Events Causing Withdrawal withIncidence 20.5%

Ca4ecoxibAdver88 Pbcek4 calOcOxiw 400 mg BIDEvanta

NSAtD(II-1664) (IW4146) (Iu31q (.=2066)—— _ _

Any Evant &1 7.1 6.8 9.7’

AMominal Pain 0.8 0.8 0.3 21’-Dyspepsia 0.6 0.8 0.8 l.r

0.6:Fti

1.1 03-0.3 : 0.3 0.4

Nauaoa 0.8 0,5 0.3 0.9PNtnb 0.2 az 0.5 0.0EaOphagaal

Ukaratbn 0.0 4.1 0.0 O.r,-*-- —1. mm,lm,,q m“mmm

“88D, W* M.-WOO

59 . . . -—

Serious Adverse Events

ActtvaPlacebo Colacoxib. COnrxol(.=2450) (11=12,646) (.=2343)——

SAESIncidence.No. (%) 34 (1.4) 341(2.7) 61 (1.8)Evmtsil 00 patimrt-ym 15,9 10.4 11.3

G.Mruintestind, No. ~) 6 (0.2) 39 (0.3) 10 (a3)Events/l 00 patbnt-yra 2.8 12 1.9

Cardiovascular, No. (%) 7 (0.3) 53 (0.4) 4 (0.1)Ewtdt 00 pmtbnt-yrs 3.3 1.6 0.7

. ml d.”,

56 . . . -—

Norlh Anmrican Arthrkb Trials

Adverse Events with 25% Incidence in AnyTreatment

Adv4rse Event

Any Event

NeactacheDyspepsiaUR71DiarrheaSinusitisAMomirrd Paint4au5aa

Placebo

(!M&l

64.6

20.26.26.73.84.32.842

Ce’koxwJ!w!!!l

W.4”

15.Wa.r8.1*5.V5.04.i3.5

Celacotib400 mg SID-k?SEL

60.2

14,5”6.1”7.06..S6.43.33.6

NSAID

(-

66.r “

14.8”12.0”-9.96.14.66.? “5.6’-

Adverse Events With an Incidence >5%

!nCirkrrc,, %

Isng.tannNorth Anmrican *

Adve?sa Evant Arthritb Triala” bbl Ttid(nD4146) (rrd466)

Naadaeho 16.6 16.0

UR71 6.1 14.1

Dyapepda 6.6 10.1

Sinusitis 5.0 92

Di=rt’ma 5.6 7.7

Aeckhntal Injury 29 7.3

AMortirul Pain 4.1 5.5

Maw 3.5 5.4

.hdu.”.* h.ku.wd *””* hr. ti-*ib! mm, Om,ZOO., Ootiwo

60 . . . -~

—-=— -.

10

Laboratory Analyses

● Hepatic

. Renal

North American 12-Week Placebo and AcdWControlltd Arthritis Tri81s

Incidence of Abnormal Renal Lab Tests (??)

Celecoxiblooand200 Neprexan

Placebo M BID 500 mg BID

Creatinlna>1.5m@dL 0.1 0.1 0.0>3.0m#dL 0.0 0.0 0.0

P.xeseiumS5 mrndxl. 0.3 0.4 0.8*.O Inlmm 0.0 0.0 0.0

uric Add<145.7 p!nelm 0.5 0.8 0.7<119 ynxofi 0.2 0.1 0.1

Pk..ban. !M3- IO* odmo.ib “ . 2CU.,,,* ..p.nll “ .s% .,072

63 . . ..-—

Two Forms of Cyclooxygenase

Arachicfonic Acid

/\Cox-1 COX-2

IP(3S 1PGX

GI Tract Inflammatory CellePlatelet ~xA) Fam#e Rw?ocAuctAmi

Kidney Kidney

Most tiseues Srdn

65 ..”. -ti–

All Arthritis Ttikl

Incidence of Elevated ALT (%)u 3x KM

1.6,❑ mlJM

:

f.4

12

1.0

0.s

0.6

0.4

L

.+

0.2 *,;..

o- *OX* Napmx. Oklohiuc Xwilrofml

(I!Alaa) (n=X.139) @1322) (I?AM3) (..327)

Conclusions: General Safety of Ceiecoxib

● Well tolerated

● Similar short and long term safety profiles

● Incidence of adverse events

- less than NSAIDS

- higher than placebo

● Laboratory tests results similar to placebo

● Incidence of elevated liver function testslower than with dic{ofenac

CA . . ..-—

North American Arthritis Tdels

Incidence of CNS/Psychiatric Adverse Events >0.5%

Plscobe CelWOxi& NSAIDAdvwsa Event

My Even!

(..1SS4) (.414S} (jmzcgs)

-—xr —2s.4” 33.T

Needeche q:InsanxliaDizzlnxaaaNypertenia ;:Anldety 0.6Mlgrehm 1.1L&t::cnye 0.5

0,4Pamsthasia 0.4

15.W 14.W2.3 2.32.01.1- :;.0.8 0.60.70.7 U“0.6 0.30.5 0.3

Wlthdrewab 0.7 1.1 0.7

.-.

Effects on Renal Function

●

✎

✎

Renal-related adverseevents

Effects on blood pressure

Renal pharmacologystudies

- healthy elderly

- chronic renalinsufficiency

67 ..”. *c—

Plasebo. and Astiwcontroilad Arihritis Trials

Effects on Blood Pressure in 12-WeekArthritis Trials

Blood Pressure (mm Hg)

n Baseline Mesn Chenge * SE——Plscebo 21e4 13W9 -1.9 * 0.3/ -1.0* 0.2

Celecoxib’ 4410 i 32i79 -0.5 * 0.3/ -0.4* 0.1

Neproxen 2150 1331T9 -0.9 * 0.3/ -0.5 * 0.2

.d.a.”.lswce. galo

T.-!mu)t. w. nd dWIh MI* ,I#wm,

69 . . . ..+ C..”..

Conclusions: Celecoxib Renal Safety

● Renal adverse events - uncommon andsimilar to NSAIDe

● No effects on blood pressure

● Transient reduction in sodium excretionsimilar to naproxen

● Low incidence of edema

● No evidence of eerious metabolicabnormalities with celecoxib or NSAIDS

71 . . ..-—

North American Adhritis Trials

Incidence of Renal Adverse Events 20.5%

Plscebo Celecoxib” NSAIDAdverse Event (n=1864) (n=4146) (n=2098)— _Any renal event 2.5 4.3’ 4.1”

Generalized Edema 0.0 0.1 0.5Peripheral Edema 1.1 2.1“ 2.1”Hypertension 0.3 0.8 0.7Aggravated Hypertension 0.4 0.6 0.3

Withdrawals 0.2 0.3 0.3

. lMms01Dmd2$+q0D cf BID

. =SWK=.”GY Whlmt *OM PI..* P .am

68 . ...-*-

Renal Pharmacology Studies

● Objectives:

- Assess effects vs. placebo and naproxen

● Design:

- Healthy elderly and patients with chronicrenal insufficiency

- Duration -7 to 10 days

● Resu Its:

- No effects on GFR

- Tranaient reduction in sodium excretion(24-48 hrs) similar to naproxen

70 . . . -—




● Rheumatoid c PlateletArthritis


of Pain

72 . . . -—

12

.——..

Effects on Platelet Function

● Bleeding-related adverseevents

● Platelet studies

- single dose

-multiple dose

73 . . . -r—

Platelet Studies● Objectives:

-Assess effects vs placebo and NSAIDS

● Design:

-5 studies in heslthy volunteers

- Duration -1 to 10 days

● Results:

- No effect at 2X the therapeutic dose:

● platelet aggregation

● TxBZ production

● bleeding time

75 ..” “-c—



● Osteoarthritis s Gastrointestinal



of Pain

77 m.. -c..”.,

North Americsn Arrhritis Trials

Incidence of Bleeding-Related AdverseEvents aO.5%

Placebo Celecoxiba NSAIDAdverse Event (n=t864) (n=4146) (n=2096)—_ _Any Blaading-Related

Event 1.6 1.8 3.6* n

Anemia 0.4 0.s 1.6* wEcchymosie 0.3 0.4 1.0” *

Withdrawals 0.0 <0.1 0.3

. wOm,BIDm.Jznom, OOEIBID

. 81,.ifle.*ffdhm.,*WM+.*- ,4 *- si*rJn-.#,dm.lwtI.Qm cdm.db p .+ 0s7“ . . . -—

Conclusions: Celecoxib Effects onPlatelet Function

● Bleeding-related adverse events -uncommon, significantly lower thanNSAIDS and similar to placebo

● No effect on serum TxB2 levels, plateletfunction or bleeding time at 2X thetherapeutic dose

‘ Platelet studies supported the COX-1sparing effect of celecoxib

I 7C ..” -—

MUCOSA Trial

O.of21

+ %*. NsAlb (n.44a91- Mlmw-ti ● NsUb (0+)

0.009

O.OQS

0.00sM p.0..310

0 30 SOSU 120 150 1s0

lime (Days)

00.+vdb.mSib”.hin.t d. h“ **” MdIWW2*24,.Z4,

78 . . ..-—

1

.-=.

13

Prospective Evaluation of GI Effects

● GI symptoms

● Endoscopy findings

-5 arthritis trials

● Analyses of UGI ulcercomplications

7CI . . . .-——

North Anwlcan &thritis ltials

GI Adverse Events Causing Withdrawal with anIncidence ~0.5yo

TraatmantGroup

Placaba Cdacoxilr NSAIDAdvama Evant (@I??!) l!@l?l(!&??!L

Any GI Evant 20 2.7 6.3’”

AMominal Pain 0.6 1.0 2.1”-Dyspapsla 0.6 0.6 1.6’Dlanhaa 0.3 0.3 0,4Nauaaa 0.6 0.5 0.9EaDphagaalUkeratlon 0.0 -al 0.6-

Endoscopic Ulcers are Surrogates forUGI Ulcer Complications

● Rationale:

- NSAIDS reduce mucosal prostaglandinaand cause ulcers

- Ulcers can result in bleeding, perforation oroutlet obstruction

- Exogenous prostaglandins reduce bothendoscopic ulcers and ulcer complicationsby -50Y. over six months”,b

North Amariean Afthritis Trials

GI Adverse Events60-

❑ U“* [r!-lbu).

by 40- ❑ Ch.ib Wm .gmq (.-41W)

, NSAJD{n.2099)

j ~. .

n~ 20- .

*.

.- .lo-

. . .

0.Al-w OvsMDsia AMominal Nauaaa Diwtiwa

Evtit - Pain

. SlmltkmLly dlfhlmt ham Pbcok P.0,4J- Simlflmily dlfhf.,,t hum wk., h @.U

80 . . ..-—

Prospective Evaluation of Gi Effects——

GI symptoms

Endoscopy findings

-5 arthritis trials

Analyses of UGI ulcercomplications

1 82 . . ..-—


PIOC* em

~—

~Waak O 2 6 12

SndOscopy x x

84 . . . -—

14

.

Mucosai Grading Scale

o12

3

4

5

6

7

No vislbis lesions (normal mucoes)

1.10 Pstschise

>10 Petschiss

1-S emslons”

S-1Osrosions

11.25 erosions

>25 srosions

UlceP

Incidence of Gastroduodenai Ulcers12-Week Studies

25 StuQy022-RA “

‘m

1s

10

5

0 L_MJlUaabolmmam

-m WpOxm(m Sm) [w SO)

‘ =m~r?4ifh-1 * a.- —. , .tcn,

87 . . . -----

Design: 6-Month RA Study

Cekxoxlb 2M nrg No

Rbm8mst0idAnmtb

~ue 1 Dkloia SR ?S ITIS BIG

I IWnk o 12 24

miouopy x

1 89 .-. --,

12-Week Endoscopy Studies

Study fJo.

021 022 Total. . _Trsstment Group (n)

Plecebo 247 231 47sCslscoxlb 50 mg BID 258 - 258Celscoxib 100 mg 910 240 240 480Cdecoxib 200 mg BID 237 23S 472

. Cebcoxib 400 mg BID - 218 218Nsproxsn 500 mg BID 233 225 4!$8

Totsl 1215 1149 23s4

--W.- .-*.,

86 . . . -—

15

Incidence of Ulcers6-Month Study

H-CL--aGeetrfc Duodenal

. Slsrinss”tlg drfa., ho. ulwOdM P.OdOY- S tins miy dltk.n, from .Am,ib Ao.M,

Cll . . . -c—

n

UGI Sak2y ve Dkbfamu and Ibuprofen Study. 071

Cumulative incidence of GastroduodenaiUlcers

0-” .2+” 0-12

Weeks

[email protected] dlmf,lt hum .Aca.lbd dklot.nm p 400,

95 ..”. -—

Design: 12-Week Serial Endoscopy Studies

Celecoxib 200 mg 910Osteoarthritis or

Rheumntokl Ar2hritls

NSAID

I 1 1Week O 4 8 12

EndoacoPy x x x x

93 . . . *c—

UGISafety vs Dklafenac ad Ibuprofen .S2udy. 071

Cumulative incidence of Gastric& DuodenaiUicers

Rationale for Serial Endoscopy Trials

● Asymptomatic ulcers may formand reheal without detection(with iong intervais betweenendoscopies)

● Seriai endoscopies might betterestimate the true incidence ofulcers

92 ..” ..—

12-Week Serial Endoscopy Studies

Study NO.

062 071 Total—. _

Treatment Group (n)Celecoxlb 200 mg BID 270 366 636Naproxen 500 mg WD 267 - 267Dklofanac 76 mg BID - 387 307Ibuprofen 800 mg TID - 346 346

Total 537 109s 1S36

ml??.d“W. $&*.amt. Zm,g,up

94 ..” .-—

I

./—=.

16

UGI Ssfely ve Nepmxen Study - 0s2

Cumulative Incidence of GastroduodenalUlcers n C*erlb 2C4m, 010

~T

, hpm..” w ., BID

-.G4”e.e” 0-12

Weeks

Celecoxib Endoscopy Studies

● Endoscopies in over 4,700 srthritispatients

● Incidence of UGI ulcers

- similar to placebo in replicate studies

- statistically lower compared to:

● naproxen

● diclofenac

● ibuprofen

99 *... -C-

Identifying UGI Ulcer Complications

● External Committeeprospectively defined UGI ulcercomplications

● Investigators reported potentialcases from OA and RA trials

● Committee reviewed andadjudicated cases

● Committee was blinded topatient, study and treatment

101. . . -—

UGISefe2y vs Napmxen Sfudy - 0S2

Cumulative Incidence of Gastric& DuodenalUlcers

❑ C!!wm.ib m q 810

ET ‘1 m Nq.un Ma ., MD

L_+_cirEo-4 &lz O-4”od’ 0.12 ‘

C&tic Duedenal

Weeks

Prospective Evaluation of GI Effects

● GI symptoms

● Endoscopy findings

-5 arthritis trials

● Analyses of UGI ulcercomplications

inn . . . ..q —

UGI Ulcer Complications Committee

● Fred Sllverstein, M.D.

s Naurang Agrawal, M.D.

● Jay Goldstein, M.D.

102. . ..-—

17

Categories of UGI Ulcer Complications

● Bleeding

● Perforation

● Gastric Outlet Obstruction

UGI Ulcer Complications Program Overview

Open Label TrialControlled

Triala NDA Safety Update

No. Studies 14 1 .

No. Patients 11,008 4499 5155

No. Patient-Yeara 1763 2672 5002

104. . . -—103 . . . -—

UGI Ulcer ComplicationsControlled Trials

No. No. K-M Patient Events/ AnnualTPUWTIOM P* Uents Event8 EsL” Years 100 Pt. Y= Incidence—— __

Placebo 1664 0 0206 0 0.00%

Cebcoxib 6276 2 0.026% 1020 0.20 0.20%

NSAIDS 2766 9 0.363% 535 lea l.66%-

“ E,wn.!” of cwnulmtk. tv.”l, nl. ttr..~h12 Wwk,

. . [email protected]”Uy dltit km” 40.xlb~~#m.ba:, .~Ol+m . . ..-c—

_-

UGI Ulcer Complications

No. No. K-M Patient Ev.nts/ AnnualPatients Events Est” Yom 100 Pt. Yrs. Incidenco—. .— — _

NDA 44e6 7 0.216% 2672 0.26 0.26%

S9myUpdat, 51E6 9 0226% 6002 0.18 0.16%

CONTROLLED 7RIALSCebcoxib 6376 2 0.026% 1020 0.20 020%

. E.*MI” 01Omwl.ll?. WNl! rti ** 1! **,

107. . . -—

UGI Ulcer ComplicationsCelecoxib Open-Label Study

No. No. K-M PWiant Events/ AnnualPatiwms Events E$t” Years 100 Pt. Ym. lllCidOIWO. . .— — —

NDA 4466 7 0216% 2672 026 0.26%

safetyupdate 5165 9 0226% 6002 0.18 0.16?4

. E.iim.t” d .UM.W.wont ,.1. tkmu~hiaMc.,lh.

106..”..*—

Conclusions: GI Effects of Celecoxib .—● NSAID GI class labeling is obviated:

- similar to placebo:

● UGI ulcers

● ulcer complication

- compared to NSAIDe showed asignificant reduction in:

● G] symptoms

● UGI ulcers

● ulcer complication

108. . ..-—

18

Celecoxib - Otierentjation Summa~

~

- Ukua- camp-s- Symptoms

Nanoataaia

- Inhibit plmchtsNapaGs

- mawtad LFrs

GaaQohtuth@

- Ukara - CompkauonsShliw to plawbo

-Raductlon inukafaandCompllcatbna

- Radudon In aymptwu

NamOat8da

-Mooffact On*alctfunctbn

- NOdaWtlOII in ~s

109 ...-—

COX-2 Inhibitors:Mechanism Based Drug Targeting

Celecoxib.

<“ \Cox-1 COX-2

I IGl Tract ArthrftiaPlatamt and Pain

+ J

Spaciflcity + Mssimal Efllwy . *$Y

110 .-.. -—

19

Documents

Celecoxib Clinical Efficacy and Safety